Regulation of ER molecular chaperone prevents bone loss in a murine model for osteoporosis

Abstract

Endoplasmic reticulum (ER) stress response is important for protein maturation in the ER. Some murine models for bone diseases have provided significant insight into the possibility that pathogenesis of osteoporosis is related to ER stress response of osteoblasts. We examined a possible correlation between osteoporosis and ER stress response. Bone specimens from 8 osteoporosis patients and 8 disease-controls were used for immunohistochemical analysis. We found that ER molecular chaperones, such as BiP (immunoglobulin heavy-chain binding protein) and PDI (protein-disulfide isomerase) are down-regulated in osteoblasts from osteoporosis patients. Based on this result, we hypothesized that up-regulation of ER molecular chaperones in osteoblasts could restore decreased bone formation in osteoporosis. Therefore, we investigated whether treatment of murine model for osteoporosis with BIX (BiP inducer X), selective inducer BiP, could prevent bone loss. We found that oral administration of BIX effectively improves decline in bone formation through the activation of folding and secretion of bone matrix proteins. Considering these results together, BIX may be a potential therapeutic agent for the prevention of bone loss in osteoporosis patients.

17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts

“…[14][15][16] It has reported that Grp78 is downregulated in osteoblasts from osteoporosis patients. 22 We demonstrated that 17b-E 2 increased Grp78 expression in responses to ER stress. Furthermore, Grp78-specific siRNA reversed the inhibition of 17b-E 2 on apoptosis as well as activation of caspase-12 and caspase-3 in ER stress, suggesting that Grp78 expression is an obligatory event in protective effect of 17b-E 2 on ER stress-induced apoptosis.…”

“…[17][18][19][20][21] ER stressinduced apoptosis of osteoblasts has also been implicated in the pathogenesis of osteoporosis. [22][23][24][25][26] Our study found that the MC3T3-E1 cells, the mouse calvaria osteoblasts, were led into the decrease of cellular viability in response to ER stress. However, pretreatment with 17b-E 2 can increase the viability of osteoblasts in ER stress in a dose-dependent manner between 0.1 nM and 100 nM and the effects plateaued at 10 nM.…”

“…[1][2][3][4][5] ER stress has been implicated as a crucial mechanism of apoptosis in various cell death processes, including osteoblast apoptosis during the development of osteoporosis. [22][23][24][25][26] Protective effects of estrogen on apoptosis of various cells have been indicated. [32][33][34] However, it is not entirely clear if estrogen can protect osteoblasts against ER stress-induced apoptosis.…”

“…ER stress has been reported to be involved in apoptosis induction that occurs during various pathophysiological progresses, including osteoporosis. [22][23][24][25][26] The ER stress is generally activated in response to various stressful conditions, such as hypoxia, the accumulation of unfolded or misfolded proteins, the alterations of calcium homeostasis, low glucose levels and others. [8][9][10] Recent reports have shown that ER stress occurs during osteogenic differentiation.…”

“…21 However, it has also reported that ER molecular chaperones, such as Grp78 and PDI (protein disulfide isomerase), are downregulated in osteoblasts from osteoporosis patients. 22 ER stress-associated osteoblast apoptosis is one of the most predominant pathogenesis of osteoporosis. [23][24][25][26] Thus, an intriguing question in osteoblasts is an outcome of survival in ER stress.…”